It has been known for decades that the chief structural materials in bone tissue are collagen and a mineral, hydroxylapatite. It is therefore, perhaps, not surprising that attempts to manufacture materials suitable for bone replacement have employed one or the other or both of these materials in some form. Various forms of collagen have been used to construct bone repair matrices (see, for example, U.S. Ser. No. 752,447, filed July 5, 1985, assigned to the same assignee). It has also been attempted to use the mineral component by itself, either as hydroxylapatite or a closely related form of calcium phosphate. See, for example, U.S. Pat. No. 3,913,229 and U.S. Pat. No. 4,097,935.
There is also literature on the use of mixtures of ceramic and collagen materials in bone repair or in dental reconstruction. At least two reports indicated that such mixtures were not effective in mediating effective bone replacement (Lemmons, J., et al, Second World Congress on Biomaterials, Washington, D.C., April 27-May 1, 1984, p. 6; Levy, P., et al, J Periodontol (1981): 303-306). Such materials were also used to construct dental prostheses as disclosed in U.S. Pat. No. 4,186,486. In these three previously cited references, the nature of the collagen used was unspecified, and it is not possible to discern the process for making the implant material or dental prostheses.
Others have used preformed collagen fibers or insoluble collagen in some form to mix with the mineral component. Batista, U.S. Pat. No. 3,443,261, prepares the mixture by using a water insoluble microcrystalline partial salt of collagen and calcium phosphate; Cruz, U.S. Pat. No. 3,767,437, also utilizes the precipitated calcium salt of collagen in the reported compositions. Gross, B. D., et al, Oral Surg (1980) 49: 21-26, used reconstituted collagen fibers in admixture with hydroxylapatite crystals. U.S. Ser. No. 717,072, filed Mar. 28, 1985, assigned to the same assignee and incorporated herein by reference, discloses methods of preparing ceramic/collagen mixtures using atelopeptide reconstituted fibrillar collagen. In addition, U.S. Pat. No. 4,516,276 to Mittelmeier employs collagen as a fleece described as a grid or network which is then dusted with apatite powder or granules, or the fiber material is mixed with mineral before being formed into layers for implantation into bone.
Others have employed collagen in solution as the organic component in forming the mixture. Perhaps the most literal approach has been that of Miyata et al, U.S. Pat. No. 4,314,380, wherein artifical bone is prepared using, as the inorganic component, animal bone which has been treated to remove the organics and then immersed in an atelopeptide collagen solution. Batista, U.S. Pat. No. 4,349,470, describes the preparation of bone prostheses by mixing a calcium phosphate mineral, which is described to include hydroxylapatite and a variety of other forms, with a protein solution in dilute hydrogen peroxide with the addition of cross-linking agents. This is described to result in a hydrogel calcium phosphate composition which can then be dried to include small uniformly dispersed bubbles. Japanese patent application No. J58/058041, published Oct. 5, 1981, describes the use of a porous calcium phosphate mineral block which is then dipped in collagen solution to coat the pores.
Other patents which relate to collagen-based bone repair preparations include the following. U.S. Pat. No. 4,488,911 to Luck et al. discloses a method of preparing dispersed fibrillar collagen which uses shear forces to order fibrils during aggregation; the method is used to prepare collagen membranes on a surface. U.S. Pat. No. 4,563,350 to Nathan discloses an admixture of a protein osteoinductive factor derived from bone with a solution containing non-fibrillar collagen. U.S. Pat. No. 4,440,750 to Glowacki et al. shows a mixture or dispersion of bone powder and fibrous collagen in aqueous solution.
It is apparent from the number and nature of the disclosures available in the art that the method of preparing the collagen, mineral, or mixed materials is of utmost importance in determining the characteristics of the product. The resulting material may or may not be effective, depending on the way in which the collagen and mineral components are handled individually and together. The present invention offers a novel preparation for collagen/mineral mixtures which results in a material of superior properties for repair of bone defects, and in particular for procedures which involve augmentation of bone structures.
The present invention also provides a collagen/mineral matrix which displays physical strength far superior to that achieved by prior art admixtures of collagen and mineral. This is evidenced, as will be described, by a product having a much higher compressive modulus than known collagen/mineral compositions.